The long-term objectives of this project are to define mechanisms of tumor- induced immune suppression of macrophage function. The innate immune system has significant potential to control cancer progression, however the specific molecular cues and pathways by which myeloid cells recognize and target cancer cells are largely undefined. Using murine models combined with phase I investigation; we have demonstrated that IFN-?-associated M1 features of tumor-associated macrophages within the lymphoma microenvironment are associated with tumor responses and prolonged survival. We now propose a multidisciplinary approach that tests our hypotheses regarding mechanisms by which the systemic as well as innate immune response within the brain may control CNS lymphoma progression. Our general strategy is to evaluate lymphoma-associated macrophages in mouse models using in vivo imaging and gene knock-out strategies to define the origin of myeloid cells in the brain that mediate tumor phagocytosis as well as to identify the key signaling pathways involved in lymphoma recognition. The specific aims are to identify the key receptors and signaling pathways used by macrophages to control lymphoma progression. We envision four goals. (1) Determine the role of the systemic myeloid response in CNS lymphoma, (2) Determine the key receptors and signaling pathways used by macrophages to recognize and elicit phagocytosis of CNS lymphoma, (3) Evaluate the impact of conditional deletions of myeloid genes on lenalidomide and rituximab-dependent responses on CNS lymphoma growth, (4) Identify factors within the CNS microenvironment that attenuate the systemic innate and adaptive immune response to CNS lymphoma. Results of these studies will have implications for a variety of disorders and cancers in which immune surveillance as well as antibody-dependent cell-mediated cytotoxicity are important means of disease control. These studies may lead to the development of new therapies that modulate macrophage programming and potentiate their anti-tumor potency as well as the adaptive immune response.